LIPID COMPOSITION OF BIPOLAR DISORDER BRAIN. Docosahexaenoic (DHA) and arachidonic acid (AA) are critical to brain function and are concentrated in synaptic membrane phospholipids. Concentrations of each of them (measured as percent of total fatty acid) were reported reduced in bipolar disorder (BD) compared with control brain. However, in postmortem BD frontal cortex obtained under strict conditions, we did not find a significant concentration difference for either fatty acid from control, whether concentration was measured per brain gram wet weight or as percent of the total fatty acid concentration. The difference from the earlier report may be due to the different sources of brain tissue, or to the fact that we measured concentrations using added authentic standards. Since we reported altered AA metabolizing enzymes in the postmortem BD, we predict that measuring AA kinetics with our PET method would show brain abnormalities in BD patients (Igarashi et al., 2010). NEUROINFLAMMATION AND EXCITOTOXICITY IN BIPOLAR DISORDER. Bipolar disorder (BD) affects 1-2 % of the US population, and is a significant cause of morbidity and mortality. Cognitive decline, symptom worsening and brain atrophy indicate progression. We showed that this progression was related to neuroinflammation and excitotoxicity. In BD compared with control frontal cortex, we reported lower protein and mRNA levels of glutamatergic N-methyl-D-aspartate (NMDA) receptor subunits NR-1 and NR-3A, and higher levels of the inflammatory cytokine interleukin (IL)-1beta, the IL-1 receptor, myeloid differentiation factor 88, nuclear factor (NF)-kappaB subunits, and of markers of activated astrocytes and microglia (GFAP, iNOS and CD11b). These data confirm the pathological processes of excitotoxicity and neuroinflammation in BD. As similar changes occur in Alzheimer disease, comparable antiinflammatory-antiexcitotoxicity therapies might be considered for both disorders (Rao et al, 2010). UPREGULATED ARACHIDONIC ACID METABOLISM IN BIPOLAR DISORDER BRAIN Based on our report that mood stabilizers given to rats downregulated markers of brain arachidonic acid (AA), we hypothesized that these markers would be elevated in bipolar disorder (BD). We confirmed this hypothesis by showing that postmortem prefrontal cortex from BD compared with control subjects demonstrated increased expression of cytosolic phospholipase A2 (cPLA2) and cyclooxygenase (COX)-2, and of their respective AP-2 and NF-kB transcription factors. These changes are consistent with our hypothesis that mood stabilizers work in BD by dampening upregulated brain AA metabolism (Kim et al., 2009). APOPTOSIS AND SYNAPTIC LOSS IN BIPOLAR DISORDER BRAIN Bipolar disorder (BD) is associated with progressive brain atrophy and cognitive decline. We related these changes to evidence of cell death and synaptic loss in BD compared with control brain. We reported increased protein and mRNA levels of pro-apoptotic factors Bax, BAD, caspase-9 and caspase-3) and decreased levels of anti-apoptotic factors (BDNF and Bcl-2) and of synaptic markers (synaptophysin and drebrin) in BD compared with control postmortem prefrontal cortex. These changes are similar to changes in Alzheimer disease, suggesting a basis for common therapeutic approaches (Kim et al., 2010). DISTURBED G-PROTEIN MEDIATED NEUROTRANSMISSION IN BIPOLAR DISORDER Bipolar disorder (BD) symptoms are considered to arise from an imbalance of neurotransmission, and synaptic function. G-proteins couple certain neuroreceptors to signaling enzymes at the synapse, and are regulated by G-protein receptor kinases (GRKs). We reported decreased protein and mRNA levels of G-protein subunits &#946;and &#947;and of GRK3 in postmortem frontal cortex from BD compared with control subjects. These results confirm synaptic dysregulation in BD. Our prior finding of positive effects of mood stabilizers on GRK3 thus may account in part for their therapeutic action in bipolar disorder (Rao et al., 2009).